Combination anti retroviral chemotherapy offers the most promising approach for sustained suppression of HIV-1 replication. By better understanding interactions among cells, virus and drugs, more effective combination strategies for prolonged HIV-1 inhibition will be developed. Specific aims of this project include the following: (1) To characterize host cellular factors, such as their state of activation, that modify responses to anti retroviral combinations. (2) To characterize viral pathogenetic factors, such as resistance genotype, syncytium-inducing phenotype, or viral load, that help to determine responses to anti retroviral combinations. (3) To characterize changes in anti-HIV-1 cell mediated immune responses in infected individuals in response to potent anti retroviral combination regimens. In vitro model systems, such as the CD4 cell outgrowth assay and the viral breakthrough replication assay will be utilized to mimic clinical conditions including acute infection, latency, and persistent productive infection. Resting cell versus activated cell models will be explored for both lymphocytes and monocyte/macrophages in order to develop strategies that can be tested in the clinic. Individualized combination strategies will be studied in patients who will be monitored for cell-mediated immune responses, e.g., cytotoxic T lymphocyte (CTL) activity, as well as for virus load. Decreases in HIV-1 load should be mirrored by increases in CTL activity, resulting in further synergy between therapy and immune responses. By combining in vitro and in vivo studies of combination regimens, it is believed that optimal therapeutic combination regimens can be developed for durable HIV-1 inhibition.